Wild-type (WT) and IL-4-/- NOD.H-2h4 mice given 0.05% NaI water develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT) with B and T cell infiltration of the thyroid, and production of anti-thyroglobulin antibody. IFN[unreadable]-/- and IFN[unreadable] receptor (R)-/- NOD.H-2h4 mice do not develop L-SAT, but all develop another autoimmune lesion characterized by thyroid epithelial cell hyperplasia and proliferation (TEC H/P). TEC H/P is very severe in 70% of IFN[unreadable]-/- mice given NaI water for 7mo. The thyroid is almost completely replaced by proliferating TEC, and there is extensive collagen deposition (fibrosis). Mice with severe TEC H/P produce anti-thyroglobulin antibodies, have low serum T4 and have some thyroid infiltrating T cells. Lymphocytes are required for development of TEC H/P. TEC H/P results from excessive proliferation of thyrocytes that occurs when IFN[unreadable] is absent. IL-4-/- mice are resistant to TEC H/P. The objective of this proposal is to define the mechanisms involved in development of severe TEC H/P and fibrosis, and determine how it can be inhibited. Thyrocytes of IFN[unreadable]-/- mice with severe TEC H/P strongly express TGF[unreadable], and all transgenic mice expressing TGF[unreadable] on TEC develop TEC H/P. These studies will test the following hypotheses: 1) TEC H/P is initiated by T cells able to migrate to the thyroid, 2) T cells produce cytokines in the thyroid (IL-4 or a cytokine that is low in IL-4-/- mice) that promote severe TEC H/P and fibrosis, and 3) overexpression of TGF[unreadable] in proliferating thyrocytes is important for development and maintenance of severe TEC H/P. These studies will use gene knockout, ie. IFN[unreadable]-/-, IFN[unreadable]-/- SCID, STAT-6-/-, and transgenic NOD.H-2h4 mice expressing TGF[unreadable] or dominant negative TGF[unreadable]RII on thyrocytes or T cells. Cell transfer experiments will be used to characterize the effector cells for TEC H/P, and to determine how cytokines such as IL-4, IL-13 and TGF[unreadable] interact with other T cells and TEC to promote development of severe TEC H/P and fibrosis. These studies will be applicable to understanding mechanisms involved in initiation and inhibition of abnormal cellular proliferation and fibrosis that can occur in the thyroid and also in other organs in some human autoimmune diseases such as systemic sclerosis and mixed connective tissue disease. This animal model provides a unique opportunity to clarify underlying mechanisms and may suggest novel therapeutic interventions for human diseases associated abnormal cellular proliferation and fibrosis.